Genetic variants of HIV and SIV that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from progenitor viruses present at early stages of infection. These variants are typically T-cell tropic, cytopathic and resistant to neutralizing antibodies. To determine how these variants influence the development of AIDS, macaques were infected with cloned SIVs representing prototype variants from intermediate and late-stage infection having biological characteristics typical of viruses found at similar stages of HIV infection in humans. Like the viruses that typically initiate HIV-1 infections, the parental virus from which these variants evolved is macrophage-tropic, non-cytopathic and non-syncytia-inducing. The levels of virus replication in macaques infected with late variants derived from blood and lymph node were >1000-fold higher than the levels in macaques infected with the non-cytopathic progenitor virus. Both late viruses were cytopathic for CD4+ lymphocytes, but the lymph node virus produced no syncytia, suggesting that a virus's ability to cause cytopathic effects in T cells is more predictive of its pathogenic potential than its phenotype. The intermediate virus, which emerged in the host because it encodes carbohydrates that allowed the virus to escape neutralizing antibodies, was intermediate in its replication and pathogenesis. Thus a neutralization escape mutant that evolves in one host may replicate more efficiently in a new host that can mount a de novo humoral immune response. These data suggest that humoral immune responses play a critical role in driving virus evolution and limiting virus replication. These studies demonstrate that sequential, phenotypic, and antigenic variants represent viruses that have become increasingly fit for replication in the host, and the data support the hypothesis that emerging variants have increased pathogenicity and drive disease progression in SIV an d HIV infection. FUNDING NIH grants RR00166 and AI34251. Kimata, J.T., Mozaffarian, A., and Overbaugh, J. A lymph node-derived cytopathic simian immunodeficiency virus Mne variant replicates in nonstimulated peripheral blood mononuclear cells. J. Virol. 72:245-256, 1998. Kimata, J.T. and Overbaugh, J. The replicative and cytopathic properties of a simian immunodeficiency virus Mne variant are determined by mutations in Gag and Env. J. Med. Primatol. 27:152, 1998 (abstract). Rudensey, L.M., Kimata, J.T., Long, E.M., Chackerian, B., and Overbaugh, J. Changes in the extracellular envelope glycoprotein of variants that evolve during the course of simian immunodeficiency virus SIVmne infection affect neutralizing antibody recognition, syncytium formation, and macrophage tropism but not replication, cytopathicity, or CCR-5 coreceptor recognition. J. Virol. 72:209-217, 1998.